Diphenylpropylamines

ABSTRACT

1,1-DIPHENYL-2-HYDROXY-3-AMINOPROPANE DERIVATIVES ARE USEFUL FOR THEIR PSYCHOTROPIC ACTIVITY AND, IN PARTICULAR ARE USEFUL AS ANTIDEPRESSANTS.

The present invention relates to derivatives of1,1-diphenyl-2-hydroxy-3-aminopropane which possess useful psychotropicactivity and which in particular, have mood modifying activity such asmood elevating activity.

Compounds of the formula (I): ##STR1## wherein A₁ and A₂ are halogen orhydrogen atoms or lower alkyl or alkoxyl groups; A₃ and A₄ are hydrogenatoms or methyl groups or together with the nitrogen atom to which theyare attached form a 5- or 6- membered rings; and B- D is a --CH₂.CH₂ --or --C:CH-- group; were shown by Jones et al [J. Med. Chem., 14, 161(1971)] to possess psychotropic activity. In that same paper, it wassuggested that compounds of the formula (II): ##STR2## could be used asintermediates in synthesis of compounds of the formula (I) but it wasnot suggested that the compounds of formula (II) might have psychotropicactivity. This may well have been because such compounds werestructurally further removed from the amitriptyline type structure thatthe compounds of formula (I) were alleged to possess.

However, U.K. Pat. No. 1,025,051 and its Patent of Addition No.1,039,454 disclose that certain of the compounds of the formula (II) andrelated butylamines have anticonvulsant, antidepressant and diureticactivity. One particulary active compound prepared in the PatentAddition was 1:1-diphenyl-3-dimethylaminopropan-1-ol and its activitywas further demonstrated by Barron et al [J. Pharm. Pharmacol., 17, 509(1965)]. The authors confirmed that the compound had considerableeffects on the central nervous system but their results show that thecompound also suffered from side effects such as anorexia, diuresis,ataxia and drowsiness. These effects were so high that the investigationof the compound was discontinued.

U.K. Pat. No. 624,118 suggested that certain of the compounds of formula(II) might possess bronchodilating properties. Such a suggestion was notunreasonable as benzylic alcohols frequently have pharmacologicalactivity and especially bronchodilatory activity. However, compounds offormula (II) have not found use as bronchodilators.

It was suggested by Lutz et al [J. Org. Chem., 12, 767 (1949)] thatcompounds of formula (II) might have antimalarial activity but noactivity of clinical significance has been reported. Greenhill [J. Chem.Soc. (C), 1298 (1970)] disclosed a series of compounds which contain analkanolic hydroxyl group in addition to or in place of the benzylichydroxyl group. The author had hoped that such compounds might possesspharmacologically useful activity because they had some relationship tothe benzylic alcohol. Benzhexol which was said to possess anti-Parkinsonactivity. However, the author was forced to report that although thecompounds had been pharmacologically tested, "no marked activity hadbeen discovered".

As may be seen in the foregoing sections, certain diphenylpropylaminederivatives have previously been examined in a search for therapeuticagents but to date none have found a place in medicine. It is thussurprising that one group of such compound has now been found to possessuseful mood modifying activity. It has further been found that thisgroup of compounds is able to produce a mood elevating effect whilebeing free or substantially free of peripheral anti-cholinergicactivity. The useful compounds may be administered in the form of anorally or parenterally administrable pharmaceutical composition.

One of the objects of this invention is to provide pharmaceuticalcompositions which on administration to mammals are capable of producinga psychotropic effect and in particular, produce a mood elevating effectwithout causing substantial side effects such as those associated withanti-cholinergic agents.

Accordingly, the present invention provides a pharmaceutical compositionwhich comprises a pharmaceutically acceptable carrier in associationwith a compound of the formula (III): ##STR3## wherein R₁ is hydrogenatom or a group R₉ or CO.R₉ wherein R₉ is a C₁₋₆ alkyl phenyl or benzylgroup or such a group ω-substituted by a group NR₁₀ R₁₁ where R₁₀ is ahydrogen atom or a methyl, ethyl or benzyl group and R₁₁ is a hydrogenatom or a methyl or ethyl group or is attached to R₁₀ so that NR₁₀ R₁₁is a pyrrolidyl, piperidyl, morpholino or hexamethylenimino group; R₂ isa hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or amethyl ethyl propyl or benzyl group; R₄ is a hydrogen atom or a methylor ethyl group or is attached to R₃ so that NR₃ R₄ is a pyrrolidyl,piperidyl, morpholino N-methylpiperazino or hexamethylenimino group R₅is a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl,propyl, butyl, benzyl, trifluoromethyl, hydroxy, methoxy, ethoxy,propoxy, benzyloxy acetoxy, propionoxy, amino, methylamino, ethylaminodimethylamino, diethylamino, carboxyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, nitro or methylthiol group R₆ R₇ and R₈ which may bethe same or different are each a hydrogen, fluorine, chlorine or bromineatom or a methyl, ethyl, methoxy, ethoxy, acetoxy, hydroxy ortrifluoromethyl group; or a salt or solvate thereof.

Acid salts of compounds of formula (III) include those ofpharmaceutically acceptable organic or inorganic acids such assulphuric, hydrochloric, hydrobromic, phosphoric, acetic, propionic,citric, malonic, malic, lactic, methanesulphonic, toluenesulphonic,tartaric or any similar acid.

Solvates if formed, are normally and preferably hydrates.

Most suitably R₁ is a hydrogen atom or a group CO.R₉ where the mostsuitable groups R₉ are the methyl, ethyl, CH₂ CH₂ NR₁₀ R₁₁ or CH₂ CH₂CH₂ NR₁₀ R₁₁ groups where R₁₀ is a hydrogen atom or a methyl or ethylgroup and R₁₁ is a methyl or ethyl group or NR₁₀ R₁₁ is a piperidylgroup

Preferably R₁ is a hydrogen atom.

Most suitably R₂ is a hydrogen atom or methyl group.

Preferably R₂ is a hydrogen atom.

Most suitably R₃ is a hydrogen atom or a methyl or benzyl group; R₄ is ahydrogen atom or a methyl or ethyl group.

Preferably R₃ is a hydrogen atom or a methyl group.

Preferably R₄ is a methyl group.

Most suitably R₅ is a hydrogen, fluorine, chlorine or bromine atom or amethyl, ethyl, trifluoromethyl, methoxy, ethoxy, acetoxy, nitro, amino,methylamino or dimethylamino group.

Most suitably R₆, R₇ and R₈ are selected from hydrogen, fluorine,chlorine or bromine atoms or methyl, methoxyl or trifluoromethyl groups.

Certain preferred compositions of this invention contain a compound ofthe formula (IV). ##STR4## wherein R₁₂ is a hydrogen atom or a methylgroup and R₁₃ R₁₄ R₁₅ and R₁₆ which may be the same or different areeach a hydrogen, fluorine, chlorine or bromine atom or a methyltrifluoromethyl or methoxyl group or a salt thereof or O-acetylderivative thereof.

Most suitably R₁₃ is a hydrogen, fluorine, chlorine or bromine atom or amethyl or trifluoromethyl group.

Most suitably R₁₄ is a hydrogen, chlorine or bromine atom.

Preferably R₁₄ is a hydrogen atom.

Most suitably R₁₅ is a hydrogen, fluorine, chlorine or bromine atom or atrifluoromethyl group.

Preferably R₁₅ is a hydrogen, fluorine or chlorine atom and mostpreferably, a hydrogen atom.

Most suitably R₁₆ is a hydrogen atom.

Compounds of formula (IV) of particularly useful activity are includedamong those compounds wherein R₁₄, R₁₅ and R₁₆ are each hydrogen atomsand R₁₃ is a hydrogen, fluorine, bromine or chlorine atom or atrifluoromethyl group.

Preferred compounds for inclusion within the compositions of thisinvention include those of formula (IV) wherein R₁₄, R₁₅ and R₁₆ areeach hydrogen atoms and R₁₃ is a hydrogen, 4-fluorine, 3- or 4-chlorine, 3-bromine atom or a 3-trifluoromethyl group.

The compounds of formula (III) have a center of assymetry at the2-carbon atom and those compounds in which the two phenyl rings aredifferently substituted have a further centre of assymetry at the1-carbon atom. A pure optical isomer may be used in the composition ofthis invention if desired or else mixtures of isomers may be used. Fullyracemic mixtures have the advantage of ease of preparation butindividual isomers or pairs of enantiomers can have certain differencesin activity and rate of onset of action that makes their use in thecompositions of the invention beneficial.

The compounds of formula (III) may advantageously be included in thesolid composition of the invention in the form of a crystalline acidaddition salt.

The compositions of the invention are specially useful in treatingadverse mental states such as, for example, depressive conditions. Forsuch treatment, the compounds are generally administered orally althoughparenteral methods of administration may also be used.

Typical oral formulations will include tablets, pills, capsules,sachets, granules, powders, chewing gum, suspensions, emulsions andsolutions particularly preferred oral formulations are tablets andcapsules. Where appropriate, the formulations may include conventionaldiluents, binding agents, dispersing agents, surface-active agents,lubricating agents, coating materials, flavouring agents, coloringagents, solvents, thickening agents, suspending agents, sweeteners orany other pharmaceutically acceptable additives, for example, gelatin,lactose, starch, talc, magnesium stearate, hydrogenated oils,polyglycols and syrups. Where the formulations are tablets or capsulesand the like, they will represent pre-measured unit doses but in thecase of granules, powders, suspensions and the like, the formulationsmay be presented as pre-measured unit doses or in multi-dose containersfrom which the appropriate unit dose may be withdrawn.

Injectable compositions may be as aqueous or non-aqueous solutions,suspensions or emulsions in a pharmaceutically acceptable liquid (e.g.sterile pyrogen-free water or parenterally acceptable oils) or mixturesof liquids which may contain bacteriostatic agents, antioxidants orother preservatives, buffers, (preferably in the physiological pH rangeof 6.5- 7.0), solutes to render the solution isotonic with the blood,thickening agents, suspending agents or other pharmaceuticallyacceptable additives. Such forms will be presented in unit dose formssuch as ampoules or disposable injection devices or in multi-dose formssuch as a bottle from which the appropriate dose may be withdrawn, or asa solid form or concentrate which can be used to quickly prepare aninjectable formulation. Suppositories containing the compound will alsocontain suitable carriers (e.g. cocoa-butter or polyglycols).

In general, the compositions of the invention will usually haveassociated with them, directions for use as anti-depressive medications.

Preferred dosage forms of the composition will be conventional tabletsor capsules containing a pre-measured dose for oral administration. Suchdosage forms will normally contain between 1 and 100 mgs of compound offormula (III) and generally between 2.5 and 75 mgs. preferably fromabout 5 to about 50 mgs. Such dosage forms will normally be taken from 1to 6 times daily. The maximum daily dose for a 70 kg. adult will notnormally exceed 360 mgs. and will not usually exceed 250 mgs. A dailydose of not more than 150 mgs. is generally preferred. Normally, thedaily dose for a 70 kg. adult will be at least 2.5 mgs., usually atleast 5 mgs.

The compositions of the invention may be prepared by conventionalmethods of mixing, blending, tabletting and the like.

Compounds of formula (III) are novel except those wherein R₂, R₅, R₆, R₇and R₈ are all hydrogen atoms and either (a) R₁ is a hydrogen atom andNR₃ R₄ is a dimethylamino, diethylamino or morpholino group or (b) R₁ isan acetyl group and NR₃ R₄ is a dimethylamino group. Such novelcompounds and their salts form a part of this invention.

The most suitable and preferred values for R₁ - R₈ of these newcompounds are the same as those stated as suitable and preferable inassociation with the compounds of formula (III).

A preferred group of novel compounds of the invention are those offormula (IV) as previously defined except that R₁₂ is not methyl whenR₁₃, R₁₄, R₁₅ and R₁₆ are all hydrogen.

The most suitable and preferred values in the compounds for R₁₃, R₁₄,R₁₅ and R₁₆ of these novel compounds are as previously defined.

As previously stated, compounds of formula (III) can exist as pureoptical isomers or mixtures of isomers. When a compound of formula (III)exists as an optical isomer, substantially free of alternative opticalisomers, it is novel and forms part of this invention. Further, if thecompounds of formula (III) are capable of existing as a mixture of fouroptical isomers, this invention includes each optical isomer insubstantially pure form or mixtures of two or three such isomers.

The present invention includes as one of its aspects, a process for thepreparation of compounds of formula (III) s hereinbefore defined exceptthat when R₂, R₅, R₆, R₇ and R₈ are all hydrogen and either (a) R₁ is ahydrogen atom and NR₃ R₄ is a dimethylamino, diethylamino or morpholinogroup, or (b) R₁ is an acetyl group and NR₃ R₄ is a dimethylamino group;which process comprises the condensation of an amine of the formula HNR₃R₄ with a compound of the formula (V): ##STR5## or a salt thereofwherein R₅, R₆, R₇ and R₈ are as defined in relation to formula (III), Yis a group displaceable by a neucleophile and X is a group CR₂ OR₁ or asuitable precursor thereof; and thereafter if desired, converting any ofthe groups R₁, R₂, R₃, R₄, R₅, R₆ R₇ and R₈ to alternative groups R₁,R₂, R₃, R₄, R₅, R₆, R₇ and R₈ by known methods and if X is a precursorof CR₂ OR₁, converting X to CR₂ OR₁ by known methods.

Suitable groups Y include chlorine, bromine or iodine atoms,pseudohalides such as azide activated oxygen atoms such as one presentin an epoxide or present in reactive esters such as methylsulphonyl ortoluene sulphonyl esters or reactive derivatives formed from a hydroxylgroup and a dehydrating agent such as a carbodiimide or imidazolediimideor the like, or any other such known good leaving groups.

If Y is a particularly good leaving group such as an iodine atom or thatproduced by the reaction of a compound wherein Y is hydroxyl with acarbodiimide, it is preferable that X is not a CR₂ OH group in orderthat self-condensation is minimized.

Suitable groups X which are precursors of the groups CR₂ OR₁ include thecarbonyl group and groups CR₂ OR¹ and CR₂ OCOR¹ where R¹ is an inertoptionally substituted hydrocarbon group such that intermediate ishydrolysable or reduceable to the alcohol. When X is a carbonyl groupreduction to the alcohol may take place under conventional conditions.

If desired, the group Y may be linked to the group X so that XCH₂ Y is a##STR6## group.

Suitable transformations of groups R₅, R₆, R₇ and R₈ include reductionand alkylative reduction of nitro groups to amino or alkylamino groups;saponification of esters, hydrogenolysis of benzyl ethers and the like.

The group OR₁ may be converted from a hydroxyl group to an ether oracyloxy group by conventional methods and the group OR₁ may be convertedfrom an ether or acyloxy group to hydroxyl group by conventional methodsof hydrolysis or hydrogenolysis or the like.

If desired, the groups R₃ and R₄ may be modified in conventional manner,for example, a primary amino group NH₂ or a secondary amino group, forexample, NHR₃, may be alkylated or acylated in conventional manner or acompound in which one or two of R₃ and R₄ are already acyl groups may beconverted to the amine by conventional methods.

Compounds which may be produced by such processes include:

3-(N-Benzyl-N-methylamino-1,1-diphenyl-propan-2-ol

3-Methylamino-1,1-diphenyl-propan-2-ol

3-(N-Benzyl-N-methylamino)-1-p-fluorophenyl-1-phenylpropan-2-ol

3-Methylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol

3-(N-Benzyl-N-methylamino)-2-methyl-1,1-diphenylpropan-2-ol

3-Methylamino-2-methyl-1,1-diphenyl-propan-2-ol

3-Dimethylamino-1,1-di-p-fluorophenyl-propan-2-ol

3-Dimethylamino-1-phenyl-1-o-tolyl-propan-2-ol

3-Dimethylamino-1-p-chlorophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-m-chlorophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-phenyl-1-p-tolyl-propan-2-ol

3-(N-Benzyl-N-methylamino)-1-phenyl-1-p-tolyl-propan-2-ol

3-Methylamino-1-phenyl-1-p-tolyl-propan-2-ol

3-Dimethylamino-1-phenyl-1-m-trifluoromethylphenyl-propan-2-ol

3-Dimethylamino-1-p-methoxyphenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-o-chlorophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-m-bromophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-(3,4-dichlorophenyl)-1-phenyl-propan-2-ol

3-N-methyl-N-ethylamino-1,1-diphenyl-propan-2-ol

3-N-piperidino-1,1-diphenyl-propan-2-ol

2-Benzoyloxy-3-dimethylamino-1,1-diphenyl-propane

3-Benzylamino-1,1-diphenyl-propan-2-ol

4-Dimethylaminobutyrate of 3-dimethylamino-1,1-diphenyl-propan-2-ol

3-Dimethylamino-1,1-diphenyl-propan-2-ol

3-Dimethylamino-1-(3,5-dichlorophenyl)-1-phenylpropan-2-ol

3-Dimethylamino-1-m-nitrophenyl-1-phenyl-propan-2-ol

3Dimethylamino-1-p-bromophenyl-1-phenyl-propan-2-ol

3-Dimethylamino-1-p-trifluoromethyl-1-phenyl-propan-2-ol

3-Dimethylamino-1,1-diphenylpropan-2-ol 2-β-dimethylaminopropionate

A particularly suitable method of preparation of compounds of formula(IV) as previously defined comprises the reaction of a compound of theformula (VI): ##STR7## With methylamine or dimethylamine or reactingwith benzylmethylamine and thereafter removing the benzyl group byhydrogenation.

Reactions strictly analogous to this are suitable for the preparation ofother compounds of formula (III) wherein CR₂ OR₁ is a CHOH group.

Such a reaction is normally carried out in an organic solvent such as alower alkanol, for example, ethanol.

The reaction may be carried out at any non-extreme low, ambient orelevated temperature but a temperature of -10° C. to 110° C. isgenerally preferred, for example, 5° C. to 60° C., for example, at roomtemperature (12°- - 18° C.).

The epoxide of formula (VI) may be prepared by the reaction of analdehyde of the formula (VII): ##STR8## wherein R₅, R₆, R₇ and R₈ are asdefined in relation to formula (IV) with 0= S(CH₃)₂ CH₂ or (CH₃)₂ s=CH₂.

This reaction may take place under the conditions outlined in Fieser &Fieser, "Reagents for Organic Synthesis", published by Wiley, 1967, atpages 314 to 318.

The compounds (VII) may be prepared by the method of Wittig et al, Chem.Ber., 94, 1373 (1961) or Mislow et al, J. Amer. Chem. Soc., 74, 1060(1952).

A process for the preparation of the aldehydes of formula (VII)comprises the contacting of an epoxide of the formula (VIII): ##STR9##wherein R₁₃, R₁₄, R₁₅ and R₁₆ are as defined in relation to formula(VII) with boron trifluoride etherate or equivalent Lewis acid.

Such a reaction will take place in an inert solvent system, for example,benzene. Although any non-extreme temperature may be used, it isgenerally preferred to use an ambient temperature as the reaction goesto completion in a few minutes under these convenient conditions.

Only a catalytic quantity of the Lewis acid need be used.

The epoxides of formula (VIII) may be prepared from the correspondingbenzophenone by reaction with O= S(CH₃)₂ = CH₂ or (CH₃)₂ s= CH₂ underconventional reaction conditions.

The useful intermediates (VII) and (VIII) when novel, also form part ofthis invention. A further particularly suitable method of preparingcompounds of formula (IV) comprises the reduction of a compound of theformula (IX): ##STR10## wherein R₁₂, R₁₃, R₁₄, R₁₅, and R₁₆ are asdefined in relation to formula (IV) except that R₁₃, R₁₄, R₁₅ and R₁₆are not all hydrogen when R₁₂ is a methyl group.

Reactions strictly analogous to this are suitable for the preparation ofother compounds of formula (III) which CR₂ OR₁ is a CHOH group.

Such a reaction may be effected by conventional means, for example, bythe use of hydrogen and a transition metal catalyst or by the action ofa complex hydride such as sodium borohydride or the like. The reactionsare normally carried out in an organic solvent such as an alkanol, forexample, methanol or ethanol. Such reactions are normally carried out atany non-extreme low, ambient or elevated temperature but a temperatureof -10° C. to 110° C. is generally preferred, for example, 5° C. to 60°C., for example at room temperature (12°-18° C.). The amine (IX) may beprepared by the reaction of dimethylamine or benzylmethylamine with acompound of the formula (X): ##STR11## wherein Y is as previouslydefined in relation to formula (V) and R₁₃, R₁₄, R₁₅ and R₁₆ are asdefined in relation to formula (IX) and when benzylmethylamine is usedcleaving the benzyl group by hydrogenation.

Such a reaction is normally carried out in an organic solvent at anon-extreme temperature.

The compounds of formula (X) wherein Y is a halogen atom may be preparedfrom the corresponding methyl ketone by the method of Stevens et al. [J.Org. Chem., 19, 538 (1954)] or analogous methods. Other compounds offormula (X) may be prepared from the bromo- or chloroketone inconventional manner.

The novel intermediates (IX) also form an aspect of this invention.

Compounds of formula (IV) may also be prepared by reductive alkylationof a corresponding N-desmethyl compound for example, by reducing amixture of formaldehyde and an amine of formula (IV) wherein R₁₂ ishydrogen or the corresponding primary amine. Compounds of formula (IV)wherein R₁₂ is a hydrogen atom may also be prepared by the catalytichydrogenation of the corresponding benzylamine.

Compounds of the formula (II) in which X is a CHOCOR₉ group may beprepared by reaction of a compound of the formula (II) in which X isCHOH and Y is a displaceable group with a reactive acylating derivativeof an acid of the formula HO.CO.R₉ or salt thereof in conventionalmanner followed by the reaction with an amine of the formula HR₃ R₄.Alternatively, such compounds may be prepared by the activation of anacid addition salt of the corresponding compound wherein X is CHOH.

In addition to being useful pharmaceutical agents in their own right,the compounds of formula (III) when prepared as a mixture of opticalisomers, also serve as useful intermediates in the preparation of theirsubstantially pure optical isomers or optically active mixture of suchisomers.

Compounds of the formula (III) may normally be resolved by conventionaltechniques used by those skilled in such work. For example, they teachuseful methods of resolution.

Compounds of the formula (IV) wherein the two optionally substitutedphenyl groups are the same can be resolved into d- and l- forms by theuse of an appropriate resolving agent such as an optically active acid.Alternatively, compounds of formula (IV) wherein the two opticallysubstituted phenyl groups are different may be separated into erythroand threo forms by, for example, fractional crystallisation of a salt.Resolution of erythro and threo forms into d- and l- isomers could thenbe achieved by the use of an appropriate resolving agent.

Particularly suitable resolving acids include (+)-mandelic and(-)-mandelic acid.

EXAMPLE 1 3-(N-Benzyl-N-methylamino)-1-1-diphenyl-propan-2-ol

Benzylmethylamine (9.7 g) was added to a solution of3-bromo-1,1-diphenylpropan-2-one (3.9 g) in ether (80 ml.) and themixture stirred for 4 hours. Extraction with dilute hydrochloric acidfollowed by basification and subsequent extraction into ether gave anoil which was chromatographed on silica gel (400 g). Elution withprogressively graded mixtures of light petroleum and ether gave3-(N-benzyl-N-methylamino)-1,1-diphenyl-propan-2-one characterised asthe hydrochloride (3.8 g., 85%), mol. 179° - 183° (from ethanol-ether).

Sodium borohydride (1.2 g) in water (15 ml) was added to a solution or3-N-benzyl-N-methylamino-1,1-diphenyl-propan-2-ol hydrochloride (3.8 g)in methanol (80 ml) and the mixture stirred for 1 hour. Concentratedhydrochloric acid (4 ml) was then added and the solution evaporatedunder reduced pressure. The residue was dissolved in water; the aqueoussolution as washed with ether, basified and extracted into ether3-(N-Benzyl-N-methylamino)-1,1-diphenyl-propan-2-ol was obtained whichwas characterised as the hydrochloride (3.1 g; 80%), m.p. 158°-161°(from ethanol-ether).

EXAMPLE 2 3-Methylamino-1,1-diphenyl-propan-2-ol

A solution of 3-N-benzyl-N-methylamino-1,1-diphenylpropan-2-olhydrochloride (2 g.) in ethanol (50 ml.) was hydrogenated at atmosphericpressure and room temperature over 5% palladium on charcoaL (200 mg) for24 hours. Filtration and evaporation gave3-methylamino-1,1-diphenylpropan-2-ol isolated as the hydrochloride (1.1g., 75%) m.p. 187° - 188° (from ethanol-ether).

EXAMPLE 33-(N-Benzyl,N-methylamino)-1-p-fluorophenyl-1-phenyl-propan-2-ol

Bromine (14.85 g) in acetic acid (200 ml.) was added dropwise to asolution of 1-p-fluorophenyl-1-phenyl-propan-2-one (20 lg.) in aceticacid (200 ml.) at 60° - 70°. After 30 minutes, the reaction mixture waspoured on to ice. Isolation through ether in the usual manner gave crude3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (28 g) which wasconverted by the procedures described in Example 1 to3-(N-Benzyl,N-methylamino)-1-p-fluorophenyl-1-phenyl-propan-2-ol (38%),m.p. 61° - 62°.

EXAMPLE 4 3-Methylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol

Hydrogenation of3-(N-benzyl,N-methylamino)-1-p-fluorophenyl-1-phenyl-propan-2-ol by theprocedure described in Example 2 gave3-methylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol isolated as thehydrochloride (70%) as a glass.

EXAMPLE 5 3-Dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol

Dimethylamine in ethanol (30 ml s of 33% solution) was added to asolution of 3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (13 g) in dryether. After 45 minutes, the reaction mixture was extracted with dilutehydrochloric acid and ether. Basification of the acid extract andsubsequent isolation through ether in the usual manner gave3-dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-one isolated as thehydrochloride (5.8 g., 53%), m.p. 219° - 220°.

Reduction with sodium borohydride by the procedure described in Example1 followed by chromatography on alumina using progressively gradedmixtures of light petroleum and ether as eluant gave3-dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-ol (76%), m.p. 55° -57°.

EXAMPLE 6 3-(N-Benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol

3-(N-Benzyl,N-methylamino)-1,1-diphenyl-propan-2-one (10 g) in dry ether(250 ml.) was added to a solution of methyl magnesium iodide (from 2.4g. magnesium and 14 2 g methyl iodide) in dry ether (250 ml.) and themixture heated at reflux for 2 hours. Saturated ammonium chloridesolution as added; isolation through ether in the usual manner gave3-(N-benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol, purifiedby chromatography on alumina using progressively graded mixtures oflight petroleum and ether as eluant and isolated as the hydrochloride(6.8 g., 65%), m.p. 121° - 124° (from ethanol-ether).

EXAMPLE 7 3-(N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol

Hydrogenation of3-(N-benzyl,N-methylamino)-2-methyl-1,1-diphenyl-propan-2-ol by theprocedure described in Example 2 gave3-methylamino-2-methyl-1,1-diphenyl-propan-2-ol isolated as thehydrochloride (79%), m.p. 272° - 273°.

EXAMPLE 8 3-Dimethylamino-1,1-di-4-fluorophenyl-propan-2-ol

Phenyl lithium (20 ml of 1M solution in ether) was added under nitrogento a stirred suspension of methoxymethyltriphenylphosphonium chloride(6.88 g) in dry ether. After 10 minutes, 4,4-difluorobenzophenone(4.56g.) in dry ether was added. After a further 2 hours,triphenylphosphine oxide was filtered off and the filtrate evaporated.The residue was chromatographed on alumina to yield1,1-di-4-fluorophenyl-2-methoxy-ethylene (3 g., 59%) which was dissolvedin a solution of 10% sulphuric acid in acetic acid (50 ml.) and allowedto stand for 30 minutes. Isolation through ether in the usual manneryielded 1,1-di-4-fluorophenylacetaldehyde which was purified bychromatography on silica gel (2.2 g., 78%).

1,1-Di-4-fluorophenylacetaldehyde (2.2 g.) in dimethyl sulphoxide (10ml.) was added under nitrogen to a solution of dimethylsulphoxoniummethylide (prepared from 2.5g. trimethylsulphoxonium iodide and 450 mgof 60% sodium hydride in 20 ml of dimethylsulphoxide) and the mixtureheated at 50° for one hour. Isolation through ether yielded crudeepoxide which was dissolved in a solution of dimethylamine in ethanol(10 mls. of 33% solution) and allowed to stand for 4 hours. Evaporationof solvent and extraction of the residue with dilute acid allowed theisolation of 3-dimethylamino-1,1-di-(4-fluorophenyl)-propan-2-ol (1.4 g55%), m.p. 56° - 58° purified by chromatography on alumina.

EXAMPLE 9 3-Dimethylamino-1-phenyl-1-o-tolyl-propan-2-ol

1-Phenyl-1-o-tolyl-acetaldehyde was reacted with dimethylsulphoxoniummethylide and the crude epoxide obtained reacted with dimethylamine bythe procedures described in Example 53-Dimethylamino-1-phenyl-1-o-tolyl-propan-2-ol was isolated as thehydrochloride, m.p. 218° - 219° (58%)

EXAMPLE 10 3-Dimethylamino-1-p-chlorophenyl-1-phenyl-propan-2-ol

p-Chlorobenzophenone (8.65 g) in dimethylsulphoxide (15 ml) was addedunder nitrogen to a solution of dimethylsulphoxanium methylide (from10.55 g of trimethylsulphoxonium iodide and 1.15 g of sodium hydride)and the mixture heated at 50° for 2 hours. Isolation through etheryielded crude 1,2-epoxy-1-p-chlorophenyl-1-phenylethone (9.0 g)

Borontrifluoride etherate (5 drops) was added to a solution of the crudeepoxide (9.0 g) in dry benzene (250 ml) After 5 minutes water was addedand the benzene layer washed with water until no longer acidic.Evaporation of solvent gave an oil which was chromatographed on silicagel; elution with progressively graded mixtures of light petroleum andether yielded p-chlorophenyl-phenylacetaldehyde (5.68 g 62%) as an oil

p-Chlorophenyl-phenylacetaldehyde (5.68 g) was reacted withdimethylsulphoxonium methylide and the crude epoxide obtained furtherreacted with dimethylamine in ethanol by the procedures described inExample 8 to give 3-dimethyl-amino-1-p-chlorophenyl-1-phenyl-propan-2-ol(2.6 g., 37% from aldehyde) as an oil

EXAMPLE 11 3-Dimethylamino-1-m-chlorophenyl-1-phenyl-propan-2-ol

An identical sequence of reactions to those described in Example 10 wasused to convert m-chlorobenzophenone to3-dimethylamino-1-m-chlorophenyl-1-phenyl-propan-2-ol isolated as thehydrochloride (24%), m.p. 118° - 123° (from ethanol-ether) Nointermediates were purified.

EXAMPLE 12 3-Dimethylamino-1-phenyl-1-p-tolyl-propan-2-ol

Following the procedures described in Examples 3 and 5,1-phenyl,1-p-tolyl-propan-2-one was converted to3-dimethylamino-1-phenyl-1-p-tolyl-propan-2-ol (30%), m.p. 55° -58°.

EXAMPLE 13 3-N-Benzyl N-methylamino)-1-phenyl-1-p-tolyl-propan-2-ol

Following the procedures described in Examples 3 and 1,1-phenyl,1-p-tolyl-propan-2-one was converted to3-(N-benzyl,N-methylamino)-1-phenyl-1-p-tolyl-propan-2-ol (25%) obtainedas an oil.

EXAMPLE 14 3-N-methylamino-1-phenyl-1-p-tolyl-propan-2-ol

Hydrogenation of3-(N-Benzyl,N-methylamino)-1-phenyl-1-p-tolyl-propan-2-ol by theprocedures described in Example 4 gave3-N-methylamino-1-phenyl-1-p-tolyl-propan-2-ol isolated as thehydrochloride. Recrystallisation from ethanol-ether gave two crops m.p.186° - 188° (35%) and m.p. 150° - 152° (36%).

EXAMPLE 153-Dimethylamino-1-phenyl-1-m-trifluoromethylphenyl-propan-2-ol

An identical sequence of reactions to those described in Example 10 wasused to convert m-trifluoromethylbenzophenone to3-dimethylamino-1-phenyl-1-m-trifluoromethylphenyl-propan-2-ol isolatedas the hydrochloride (5%), m.p. 110° - 113°.

EXAMPLE 16 3-Dimethylamino-1-p-methoxyphenyl-1-phenyl-propan-2ol

An identical sequence of reactions to those described in Example 10 wasused to convert p-methoxybenzophenone to3-dimethylamino-1-p-methoxyphenyl-1-phenyl-propan-2-ol isolated as thehydrochloride (13%) as a glass.

EXAMPLE 17 3-Dimethylamino-1-o-chlorophenyl-1-phenyl-propan-2-ol

An identical sequence of reactions to those described in Example 10 wasused to convert o-chlorobenzophenone to3-dimethylamino-1-o-chlorophenyl-1-phenyl-propan-2-ol isolated as thehydrochloride (34%, m.p. 216° - 218° (from ethanol-ether.

EXAMPLE 18 3-Dimethylamino-1-m-bromophenyl-1-phenyl-propan-2-ol

An identical sequence of reactions to those described in Example 10 wasused to convert m-bromobenzophenone to3-dimethylamino-1m-bromophenyl-1-phenyl-propan-2-ol isolated as thehydrochloride (22%), m.p. 128° -138° (from ethanol-ether).

EXAMPLE 19 3-Dimethylamino-1-(3,4-dichlorophenyl)-1-phenyl-propan-2-ol

An identical sequence of reactions to those described in Example 10 wasused to convert 3,4-dichlorobenzophenone to3-dimethylamino-1-(3,4-dichlorophenyl)-1-phenyl-propan-2-ol isolated asthe hydrochloride (3%) as a glass.

EXAMPLE 20 3-(N-Methyl-N-ethylamino)-1,1 -diphenyl-propan-2-ol

Sodium borohydride (1 52 g.) in sodium hydroxide solution (15 ml. 0.02M)was added to 1,1-diphenyl-3-bromo-propan-2-one (12 g.) in methanol (50ml.), and the solution was stirred for one hour. Isolation through etherin the usual manner afforded 1,1-diphenyl-3-bromo-propan-2-ol (10 4 g.86%) as an oil.

Excess N methyl-N-ethylamine was added to a solution of 1,1-diphenyl-3-bromo-propan-2-ol (2 g.) in ethanol. After 60 hours thesolution was evaporated and the residue was evaporated and the residuedissolved in dilute hydrochloric acid and ether. Basification of theacid extract and subsequent isolation through ether in the usual mannergave 3-(N-methyl-N-ethylamino)-1,1 -diphenyl-propan-2-ol isolated as thehydrochloride (1 25 g., 60%), m.p. 159° - 161°.

EXAMPLE 21 3-N-Piperidino-1,1 -dipheyl-propan-2ol

Diphenylacetaldehyde was converted to 1,1-diphenyl-2,3-epoxy-propan(90%) using dimethylsulphoxonium methylide by the procedure described inExample 8. Further reaction of the epoxide with piperidine, also asdescribed in Example 8 gave 3-N-piperidino-1,1-diphenyl-propan-2-olisolated as the hydrochloride (57%), m.p. 194° - 196°.

EXAMPLE 22 2-Benzoyloxy-3-dimethylamino-1,1-diphenyl-propane

Benzoyl chloride (1.49 g.) was added to3-dimethylamino-1,1-diphenyl-propan-2-ol (2.55 g.) in dry pyridine (10ml.) and the solution allowed to stand for 4 hours. Pyridine was removedby evaporation and the residue dissolved in dilute hydrochloric acid andether. Basification of the acid extract and isolation through ether inthe usual manner gave 2-benzoyloxy-3-dimethylamino-1,1-diphenylpropane(3.47 g., 99%), m.p. 90° - 91°.

EXAMPLE 23 3-Benzylamino-1,1-diphenyl-propan-2-ol

1,1-Diphenyl-2,3-epoxy-propane, prepared as described in Example 21, wasreacted with benzylamine in ethanol by a procedure analogous to thatdescribed in Example 8, 3-benzylamino-1,1-diphenyl-propan-2-ol (33%),m.p. 123° - 124° was obtained.

EXAMPLE 24 3-Dimethylamino-1,1-diphenyl-propan-2-ol

(a) 2-Acetoxy-3-dimethylamino-1,1-diphenyl-propane (200 mg) wasdissolved in methanolic potassium hydroxide (5% 10 ml.) and the solutionallowed to stand overnight. Solvent was evaporated and the residuedissolved in ether and water. The ether extract was dried and evaporatedto give 3-dimethylamino-1,1-diphenyl-propan-2-ol (170 mg., 97%), m.p.72° - 73°.

(b) 1,1-Diphenyl-3-bromopropan-2-ol (500 mg.) prepared as described inExample 20 was treated with excess dimethylamine in ethanol and thesolution allowed to stand overnight. Solvent was removed by evaporationand the residue dissolved in dilute hydrochloric acid and ether.Basification of the acid extract and isolation through ether in theusual manner gave 3-dimethylamino-1,1-diphenyl-propan-2-ol (330 mg.,75%), m.p. 72° - 73°.

(c) 1,1-Diphenyl-2,3-epoxy-propane prepared as described in Example 21,was further reacted with dimethylamine in ethanol by the proceduredescribed in Example 8 to give 3-dimethylamino-1,1-diphenyl-propan-2-ol(90%), m.p. 72° - 73°.

EXAMPLE 25 4-Diethylaminobutyrate of3-dimethylamino-1,1-diphenyl-propan-2-ol

A solution of 3-dimethylamino-1,1-diphenyl-propan-2-ol (2.55 g.),4-diethylaminobutyric acid hydrochloride (1.95 g.) anddicyclohexylcarbodiimide (2.1 g.) in dichloromethane (50 ml.) wasstirred at room temperature for 5 days. Dicyclohexylurea was filteredoff and the filtrate concentrated. The residue was dissolved in dilutehydrochloric acid and ether. The acid extract was basified; isolationthrough ether in the normal manner gave an oil which was chromatographedas alumina (200 g.). Elution with progressively graded mixtures of lightpetroleum and ether gave the 4-diethylaminobutyrate of3-dimethylamino-1,1-diphenyl-propan-2-ol isolated as the dihydrochloride(41%) as a glass.

EXAMPLE 26: (-)-3-Dimethylamino-1,1-diphenyl-propan-2-ol

Equimolar quantities of 3-dimethylamino-1,1-diphenylpropan-2-ol andD(-)-mandelic acid were dissolved in ethyl acetate and the solutionevaporated. The resulting mandelate was recrystallised 5 times fromethyl acetate using 30-35 mls of ethyl acetate per gram of mandelate,the melting point of rising from 140°-143° to a constant 153°-154°.Regeneration of the free base gave(-)-3-dimethylamino-1,1-diphenyl-propan-2-ol, m.p. 61° - 62°, [α]_(D) ²⁰-56° (c 1.6 in EtOH) converted to the hydrobromide, m.p. 184° - 185°.

EXAMPLE 27 (+)-3-Dimethylamino-1,1-diphenyl-propan-2-ol

The mother liquors from the preparation of the (-) isomer in Example 25were combined and evaporated. The free base enriched in (+)isomer, wasregenerated in the usual manner Equimolar quantities of free base andD(+)-mandelic acid were dissolved in ethyl acetate and the solutionevaporated. The resulting mandelate was recrystallised 4 times fromethyl acetate using 30-35 mls. of ethyl acetate per gram of mandelate,the melting point rising to a constant 153°-154°. Regeneration of thefree base gave (+)-3-dimethylamino-1,1-diphenyl-propan-2-ol, m.p.60°-61°, [α]_(D) ²⁰ + 56° (c 1.6 in EtOH) converted to the hydrobromide,m.p. 184° - 185°.

EXAMPLE - PHARMACOLOGY 1

(a) Tests Used

1. Prevention of Reserpine Hypothermia for Potential Antidepressant

The method of Spencer [Antidepressant Drugs, 194(1967)] was used. Groupsof ten mice are given oral doses of test compound 24, 18 and 2 hoursbefore an intravenous injection of reserpine base (Serpasil). Oraltemperatures of the mice are taken immediately before administration ofreserpine and then, 2, 4, 6 and 24 hours afterwards.

Mean temperatures of groups given test compounds are compared withreserpinised controls using a Students t test. Compounds causing asignificant difference at the level P<0.001 are considered active. Inorder to quantify anti-reserpine activity, cumulative temparaturedifferences from controls at 6 hours and 24 hours (Δ⁶ and Δ²⁴) arecalculated. Thus, the larger the figure for Δ⁶ and Δ²⁴ the more activethe compound Δ⁶ should be at least 5° C. for the compound to beconsidered active and at least 8° C. to have a highly acceptable levelof activity.

2. Reversal of Reserpine Hypothermia

Groups of ten mice are injected intravenously with 1.5 mg/kg Reserpinebase. Seventeen hours later the oral temperatures of the mice are takenand various doses of test compounds or vehicle given subcutaneously.Temperatures are taken 1, 2, 4, 6 and 24 hours later and the results areanalysed as in test 1 (The subcutaneous route is used for convenience asthe very depressed reserpinised mice cannot be reliably dosed orally).

3. Inhibition of Noradrenaline and 5-Hydroxytryptramine Uptake in vitro

Synaptosomes are isolated from the brains of male Wistar rats (150-170g.) and monoamine uptake determined by the method of Snyder and Coyle(1968) [Synyder S.H. and Coyle J. T. J. Pharmac. exp. Ther. 165 (1968)78-86]. Uptake was determined over a ten minute period instead of thenormal five minutes.

4. Mydriatic Response in Mice

Groups of five mice are pre-selected for uniformity of pupil diameterusing a binocular microscope with a calibrated eye-piece. Pupil sizesare measured at various intervals after an intraperitoneal injection oftest compound and at the peak time a curve plotted of percentageincrease in pupil diameter versus log dose. From this the dose causing a200% increase in pupil size (this lies on the linear part of the curve)is found.

(Anticholinergic compounds cause an increase in pupil diameter(mydriasis) thus the higher the dose quoted, the lower the probable sideeffect).

5. pA₂ Determination on Guinea Pig Ileum

This experiment measures in vitro antagonism to Acetylcholine (apossible side effect) and the lower the pA₂ the more desirable thecompound. pA_(x) is defined as the negative logarithum base 10 of themolar concentration of antagonist which will reduce the effect of amultiple dose (X) of an active drug to that of a single dose. It is thusa means of expressing anticholinergic activity which is independent ofthe dose of Acetylcholine and the piece of tissue used.

The method used is similar to that of Schild, [Brit. J. Pharmacol 14(1959) 48] the tissue being bathed in Tyrode solution and a doseresponse curved for Acetylcholine being obtained. This dose responsecurve is repeated in the presence of various doses of test compound andthe pA₂ is found from a plot of (log dose ratio-1) against molarconcentration of the test compound.

6. Animals and Solutions

Carworth Europe male mice are used for all experiments apart from thatusing the cat nictitating membrane and test compounds are administeredorally as solutions in distilled water. Compounds for intravenousadministration are dissolved in 0.9% saline apart from Reserpine whichis dissolved is dilute acetic acid buffered to pH5. Unless otherwisestated, the dosing interval is one hour.

(b) Results

1. Prevention of Reserpine Hypothermia

Compounds of the formulae E1 and E2. ##STR12##

    (Ph).sub.2 CH-- CA.sub.10 OA.sub.11 -- CH.sub.2 -- A.sub.12 -- HCl (E2)

and the standard compounds Imiprimine and Amitryptyline were tested asdescribed in al. The results are shown in Tables 1 and 2.

                  TABLE 1                                                         ______________________________________                                                           Reserpine Prevention                                                          Test                                                                                          Dose                                                                          mg/                                        A.sub.5                                                                              A.sub.6                                                                              A.sub.7                                                                              A.sub.8                                                                           A.sub.9                                                                            Salt kg   Δ6(° C)                                                                Δ24(° C)           ______________________________________                                        CH.sub.3                                                                             CH.sub.3                                                                             H      H   H    HBr  20   13    19                              CH.sub.2 C.sub.6 H.sub.5                                                             CH.sub.3                                                                             H      H   H    HCl  30   10    11                              CH.sub.2 C.sub.6 H.sub.5                                                             CH.sub.3                                                                             H      H   F         30    9    11                              CH.sub.3                                                                             CH.sub.3                                                                             H      H   F         20   11    15                              H      CH.sub.3                                                                             H      H   F         30   12    21                              CH.sub.3                                                                             CH.sub.3                                                                             H      H   Cl        30   13    22                              CH.sub.3                                                                             CH.sub.3                                                                             H      Cl  H    HCl  20   10    17                              CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                             H   H    HCl  30   11    14                              CH.sub.3                                                                             H      H      H   CH.sub.3                                                                           HCl  100   6     6                              C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      H      H   H    HCl  30   11    11                              CH.sub.3                                                                             H      H      H   H    HCl  20   >10   >10                             ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                        Reserpine Prevention                                                          Test                                                                                    Dose                                                A.sub.10                                                                           A.sub.11                                                                              A.sub.12     mg/kg Δ6(° C)                                                                 Δ24(° C)                  ______________________________________                                        CH.sub.3                                                                           H       NHCH.sub.3   30    7      13                                     CH.sub.3                                                                           H       N(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5                                                        100   6       8                                     H    H       morpholino   100   10     10                                     H    H       piperidine   100   9      10                                     H    COCH.sub.3                                                                            N(CH.sub.3).sub.2                                                                          20    >10    >10                                    Imiprimine hydrochloride                                                                        30      10       17                                         Amitriptyline hydrochloride                                                                     30      12       22                                         ______________________________________                                    

2. Reversal of Reserpine Hypothermia

Using the test described in a 2, the following results were found forcertain compounds of formula E1:

                  TABLE 3                                                         ______________________________________                                                       Reserpine Reversal Test                                        A.sub.5                                                                            A.sub.6                                                                              A.sub.7                                                                             A.sub.8                                                                           A.sub.9                                                                           Salt Dose mg/kg                                                                            Δ.sup.6 (° C)                                                           Δ.sup.24 (°        ______________________________________                                                                                      C)                              CH.sub.3                                                                           CH.sub.3                                                                             H     H   H   HBr  20      14     22                              CH.sub.3                                                                           CH.sub.3                                                                             H     H   F   HCl  25      17     23                              CH.sub.3                                                                           CH.sub.3                                                                             H     H   Cl       30      9      11                              Imipramine    HCl    10        18     18                                      ______________________________________                                    

3. Inhibition of Noradrenaline and 5-Hydroxytryptamine

Using the test described in a 3, the following results were found forcertain compounds of formula E1:

                  TABLE 4                                                         ______________________________________                                                       Inhibition of Monoamine                                                       Uptake                                                                                        Molar      NA   5HT                            A.sub.5                                                                            A.sub.6                                                                              A.sub.7                                                                             A.sub.8                                                                           A.sub.9                                                                           Salt Concentration                                                                            (%)  (%)                            ______________________________________                                        H    CH.sub.3                                                                             H     H   H   HCl  10.sup..sup.-5                                                                           85                                                                 10.sup..sup.-6                                                                           65                                  CH.sub.3                                                                           CH.sub.3                                                                             H     H   F        10.sup..sup.-5                                                                           80   85                                                            10.sup..sup.-6                                                                           59   60                             Imipramine    HCl    10.sup..sup.-5                                                                             85   90                                                          10.sup..sup.-6                                                                             56   55                                     ______________________________________                                    

4. Mydriatic Response in Mice and pA₂ in Guinea Pigs

Compounds of the formula E1 were tested as described in a 4 and a 5 toprovide the results shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        Anticholinergic Side                                                          Effect                                                                                                        Mydriasis-Dose                                                                to cause 200%                                                                             pA.sub.2 on                       A.sub.5                                                                            A.sub.6                                                                              A.sub.7                                                                             A.sub.8                                                                           A.sub.9                                                                           Salt  effect-mg/kg                                                                              Iillium                           ______________________________________                                        CH.sub.3                                                                           CH.sub.3                                                                             H     H   H   HBr   41          5                                 H    CH.sub.3                                                                             H     H   H   HCl   114         5                                 CH.sub.3                                                                           H      H     H   F   HCl   92          4                                 CH.sub.3                                                                           CH.sub.3                                                                             H     H   Cl  HCl   40          5                                 Imipramine    HCl     18            9                                         Amitryptyline HCl      6            8                                         ______________________________________                                    

EXAMPLE - PHARMACOLOGY 2

(a) Tests Used

The Reserpine Prevention, Reserpine Reversal and Noradrenaline UptakeInhibition tests were carried out as described in the previous Example.The Mydriasis test was also as described in the previous Example butusing 20 mg/kg doses of each compound after which a curve was plotted ofpercentage increase in pupil diameter versus time and the percentageincrease was integrated with respect to time for 0-120 minutes afterdosing and the result expressed as a percentage.

(b) Results

(±)-3-Dimethylamino-1,1-diphenylpropan-2-ol is Compound A

(+)-3-Dimethylamino- 1,1-diphenylpropan-2-ol is Compound B

(-)- 3-Dimethylamino-1,1-diphenylpropan-2-ol is Compound C

    ______________________________________                                        Inhibition of Noradrenaline                                                                         Mydriasis Integral                                      Uptake In Vitro       Percent 120 Mins                                        ______________________________________                                        Compound                                                                              Molar Conc.  %        Dose    %                                       ______________________________________                                        A       10.sup..sup.-6                                                                             63       20mg/kg.                                                                              7400                                    B       10.sup..sup.-6                                                                             40       20mg/kg.                                                                              12600                                   C       10.sup..sup.-6                                                                             64       20mg/kg.                                                                              6700                                    ______________________________________                                    

    ______________________________________                                                 Reserpine Prevention                                                                       Reserpine Reversal                                      Compound                                                                              Dose   Δ.sup.6 (° C)                                                             Δ.sup.24 (° C)                                                           Δ.sup.6 (° C)                                                           Δ.sup.24 (° C)            ______________________________________                                        A       10     12       16      16     20                                             20     15       19      14     17                                             40     15       22      15     20                                     B       10     12       15      16     27                                             20     16       23      15     19                                             40     16       25      13     19                                     C       10     11       17       6      3                                             20     13       19      16     19                                             40     12       19      13     20                                     ______________________________________                                    

These results indicate that the (-)-isomer shows fewer peripheralanticholinergic effects than the (+)-isomer and that (+)-isomer is moreactive than the (-)-isomer on the Reserpine Reversal Test at low dosesbut that the two isomers have roughly equal effects on the ReserpinePrevention tests.

What we claim is:
 1. A compound of the formula ##STR13## or apharmaceutically acceptable acid addition salt thereof, wherein R₁₂ ishydrogen or methyl, andR₁₃ is fluorine, chlorine or bromine.
 2. Acompound according to claim 1 in the form of a diastereoisomer.
 3. Acompound according to claim 1 wherein R₁₃ is 4-fluorine.
 4. A compoundaccording to claim 1 wherein R₁₃ is 3-chlorine.
 5. A compound accordingto claim 1 wherein R₁₃ is 4-chlorine.
 6. A compound according to claim 1wherein R₁₃ is 3-bromine.
 7. A compound according to claim 1 which is inthe form of a racemate.
 8. A compound according to claim 1 which is anenantiomer.
 9. A compound according to claim 1 wherein R₁₂ is hydrogen.10. A compound according to claim 1 wherein R₁₂ is methyl.
 11. Thecompound according to claim 1 which is3-methylamino-1-(p-fluorophenyl)-1-phenyl-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 12. The compoundaccording to claim 11 in the form of a pharmaceutically acceptable acidaddition salt.
 13. The compound according to claim 1 which is3-dimethylamino-1-(p-fluorophenyl)-1-phenyl-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 14. The compoundaccording to claim 13 in the form of a pharmaceutically acceptable acidaddition salt.
 15. The compound according to claim 1 which is3-dimethylamino-1-(p-chlorophenyl)-1-phenyl-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 16. The compoundaccording to claim 15 in the form of a pharmaceutically acceptable acidaddition salt.
 17. The compound according to claim 1 which is3-dimethylamino-1-(m-chlorophenyl)-1-phenyl propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 18. The compoundaccording to claim 17 in the form of a pharmaceutically acceptable acidaddition slat.
 19. The compound according to claim 1 which is3-dimethylamino-1-(o-chlorophenyl)-1-phenyl-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 20. The compoundaccording to claim 19 in the form of a pharmaceutically acceptable acidaddition salt.
 21. The compound according to claim 1 which is3-dimethylamino-1-(m-bromophenyl)-1-phenyl-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 22. The compoundaccording to claim 21 in the form of a pharmaceutically acceptable acidaddition salt.
 23. A compound of the formula ##STR14## ##STR15## or apharmaceutically acceptable acid addition salt thereof, wherein R₁₂ ishydrogen or methyl, andR₁₃ is trifluoromethyl.
 24. A compound accordingto claim 23 in the form of a diastereoisomer.
 25. A compound accordingto claim 23 in the form of an enantiomer.
 26. A compound according toclaim 23 in the form of a racemate.
 27. A compound according to claim 23wherein R₁₃ is 3-trifluoromethyl.
 28. The compound according to claim 23which is 3-dimethylamino-1-(m-trifluoromethylphenyl)-propan-2-ol or apharmaceutically acceptable acid addition salt thereof.
 29. The compoundaccording to claim 28 in the form of a pharmaceutically acceptable acidaddition salt.